Human aquaporin 4 281-300 is the immunodominant linear determinant in the context of HLA-DRB1*03: 01: Relevance for diagnosing and monitoring patients with neuromyelitis optica

Benjamine Arellano, Rehana Hussain, Tresa Zacharias, Jane Yoon, Chella David, Sima Zein, Lawrence Steinman, Thomas Forsthuber, Benjamin M. Greenberg, Doris Lambracht-Washington, Alanna M. Ritchie, Jeffrey L. Bennett, Olaf Stüve

Research output: Contribution to journalArticle

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Abstract

Objective: To identify linear determinants of human aquaporin 4 (hAQP4) in the context of HLA-DRB1&z.ast;03:01. Design: In this controlled study with humanized experimental animals, HLA-DRB1&z.ast;03:01 transgenic mice were immunized with whole-protein hAQP4 emulsified in complete Freund adjuvant. To test T-cell responses, lymph node cells and splenocytes were cultured in vitro with synthetic peptides 20 amino acids long that overlap by 10 amino acids across the entirety of hAQP4. The frequency of interferon γ, interleukin (IL) 17, granulocyte-macrophage colony-stimulating factor, and IL-5-secreting CD4 + T cells was determined by the enzyme-linked immunosorbent sport assay. Quantitative immunofluorescence microscopy was performed to determine whether hAQP4 281-300 inhibits the binding of anti-hAQP4 recombinant antibody to surface full-length hAQP4. Setting: Academic neuroimmunology laboratories. Subjects: Humanized HLA-DRB1*03:01 +/+ H-2b -/- transgenic mice on a B10 background. Results: Peptide hAQP4 281-300 generated a significantly (P<.01) greater T H1 and T H17 immune response than any of the other linear peptides screened. This 20mer peptide contains 2 dominant immunogenic 15mer peptides. hAQP4 284-298 induced predominantly an IL-17 and granulocyte- macrophage colony-stimulating factor T H cell phenotype, whereas hAQP4285-299 resulted in a higher frequency of T H1 cells. hAQP4 281-300 did not interfere with recombinant AQP4 autoantibody binding. Conclusions: hAQP4 281-330 is the dominant linear immunogenic determinant of hAQP4 in the context of HLADRB1&z.ast; 03:01. Within hAQP4 281- 330 are 2 dominant immunogenic determinants that induce differential T H phenotypes. hAQP4 determinants identified in this study can serve as diagnostic biomarkers in patients with neuromyelitis optica and may facilitate the monitoring of treatment responses to pharmacotherapies.

Original languageEnglish (US)
Pages (from-to)1125-1131
Number of pages7
JournalArchives of Neurology
Volume69
Issue number9
DOIs
StatePublished - Sep 2012

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Aquaporin 4
Neuromyelitis Optica
Immunodominant Epitopes
Physiologic Monitoring
Peptides
HLA-DRB1 Chains
Interleukin-17
Granulocyte-Macrophage Colony-Stimulating Factor
Transgenic Mice
HLA-DRB1*03:01 antigen
Monitoring
T-Lymphocytes
Phenotype
Amino Acids
Freund's Adjuvant
Interleukin-5
Fluorescence Microscopy
Autoantibodies
Interferons
Sports

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

Human aquaporin 4 281-300 is the immunodominant linear determinant in the context of HLA-DRB1*03 : 01: Relevance for diagnosing and monitoring patients with neuromyelitis optica. / Arellano, Benjamine; Hussain, Rehana; Zacharias, Tresa; Yoon, Jane; David, Chella; Zein, Sima; Steinman, Lawrence; Forsthuber, Thomas; Greenberg, Benjamin M.; Lambracht-Washington, Doris; Ritchie, Alanna M.; Bennett, Jeffrey L.; Stüve, Olaf.

In: Archives of Neurology, Vol. 69, No. 9, 09.2012, p. 1125-1131.

Research output: Contribution to journalArticle

Arellano, B, Hussain, R, Zacharias, T, Yoon, J, David, C, Zein, S, Steinman, L, Forsthuber, T, Greenberg, BM, Lambracht-Washington, D, Ritchie, AM, Bennett, JL & Stüve, O 2012, 'Human aquaporin 4 281-300 is the immunodominant linear determinant in the context of HLA-DRB1*03: 01: Relevance for diagnosing and monitoring patients with neuromyelitis optica', Archives of Neurology, vol. 69, no. 9, pp. 1125-1131. https://doi.org/10.1001/archneurol.2012.1300
Arellano, Benjamine ; Hussain, Rehana ; Zacharias, Tresa ; Yoon, Jane ; David, Chella ; Zein, Sima ; Steinman, Lawrence ; Forsthuber, Thomas ; Greenberg, Benjamin M. ; Lambracht-Washington, Doris ; Ritchie, Alanna M. ; Bennett, Jeffrey L. ; Stüve, Olaf. / Human aquaporin 4 281-300 is the immunodominant linear determinant in the context of HLA-DRB1*03 : 01: Relevance for diagnosing and monitoring patients with neuromyelitis optica. In: Archives of Neurology. 2012 ; Vol. 69, No. 9. pp. 1125-1131.
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abstract = "Objective: To identify linear determinants of human aquaporin 4 (hAQP4) in the context of HLA-DRB1&z.ast;03:01. Design: In this controlled study with humanized experimental animals, HLA-DRB1&z.ast;03:01 transgenic mice were immunized with whole-protein hAQP4 emulsified in complete Freund adjuvant. To test T-cell responses, lymph node cells and splenocytes were cultured in vitro with synthetic peptides 20 amino acids long that overlap by 10 amino acids across the entirety of hAQP4. The frequency of interferon γ, interleukin (IL) 17, granulocyte-macrophage colony-stimulating factor, and IL-5-secreting CD4 + T cells was determined by the enzyme-linked immunosorbent sport assay. Quantitative immunofluorescence microscopy was performed to determine whether hAQP4 281-300 inhibits the binding of anti-hAQP4 recombinant antibody to surface full-length hAQP4. Setting: Academic neuroimmunology laboratories. Subjects: Humanized HLA-DRB1*03:01 +/+ H-2b -/- transgenic mice on a B10 background. Results: Peptide hAQP4 281-300 generated a significantly (P<.01) greater T H1 and T H17 immune response than any of the other linear peptides screened. This 20mer peptide contains 2 dominant immunogenic 15mer peptides. hAQP4 284-298 induced predominantly an IL-17 and granulocyte- macrophage colony-stimulating factor T H cell phenotype, whereas hAQP4285-299 resulted in a higher frequency of T H1 cells. hAQP4 281-300 did not interfere with recombinant AQP4 autoantibody binding. Conclusions: hAQP4 281-330 is the dominant linear immunogenic determinant of hAQP4 in the context of HLADRB1&z.ast; 03:01. Within hAQP4 281- 330 are 2 dominant immunogenic determinants that induce differential T H phenotypes. hAQP4 determinants identified in this study can serve as diagnostic biomarkers in patients with neuromyelitis optica and may facilitate the monitoring of treatment responses to pharmacotherapies.",
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T1 - Human aquaporin 4 281-300 is the immunodominant linear determinant in the context of HLA-DRB1*03

T2 - 01: Relevance for diagnosing and monitoring patients with neuromyelitis optica

AU - Arellano, Benjamine

AU - Hussain, Rehana

AU - Zacharias, Tresa

AU - Yoon, Jane

AU - David, Chella

AU - Zein, Sima

AU - Steinman, Lawrence

AU - Forsthuber, Thomas

AU - Greenberg, Benjamin M.

AU - Lambracht-Washington, Doris

AU - Ritchie, Alanna M.

AU - Bennett, Jeffrey L.

AU - Stüve, Olaf

PY - 2012/9

Y1 - 2012/9

N2 - Objective: To identify linear determinants of human aquaporin 4 (hAQP4) in the context of HLA-DRB1&z.ast;03:01. Design: In this controlled study with humanized experimental animals, HLA-DRB1&z.ast;03:01 transgenic mice were immunized with whole-protein hAQP4 emulsified in complete Freund adjuvant. To test T-cell responses, lymph node cells and splenocytes were cultured in vitro with synthetic peptides 20 amino acids long that overlap by 10 amino acids across the entirety of hAQP4. The frequency of interferon γ, interleukin (IL) 17, granulocyte-macrophage colony-stimulating factor, and IL-5-secreting CD4 + T cells was determined by the enzyme-linked immunosorbent sport assay. Quantitative immunofluorescence microscopy was performed to determine whether hAQP4 281-300 inhibits the binding of anti-hAQP4 recombinant antibody to surface full-length hAQP4. Setting: Academic neuroimmunology laboratories. Subjects: Humanized HLA-DRB1*03:01 +/+ H-2b -/- transgenic mice on a B10 background. Results: Peptide hAQP4 281-300 generated a significantly (P<.01) greater T H1 and T H17 immune response than any of the other linear peptides screened. This 20mer peptide contains 2 dominant immunogenic 15mer peptides. hAQP4 284-298 induced predominantly an IL-17 and granulocyte- macrophage colony-stimulating factor T H cell phenotype, whereas hAQP4285-299 resulted in a higher frequency of T H1 cells. hAQP4 281-300 did not interfere with recombinant AQP4 autoantibody binding. Conclusions: hAQP4 281-330 is the dominant linear immunogenic determinant of hAQP4 in the context of HLADRB1&z.ast; 03:01. Within hAQP4 281- 330 are 2 dominant immunogenic determinants that induce differential T H phenotypes. hAQP4 determinants identified in this study can serve as diagnostic biomarkers in patients with neuromyelitis optica and may facilitate the monitoring of treatment responses to pharmacotherapies.

AB - Objective: To identify linear determinants of human aquaporin 4 (hAQP4) in the context of HLA-DRB1&z.ast;03:01. Design: In this controlled study with humanized experimental animals, HLA-DRB1&z.ast;03:01 transgenic mice were immunized with whole-protein hAQP4 emulsified in complete Freund adjuvant. To test T-cell responses, lymph node cells and splenocytes were cultured in vitro with synthetic peptides 20 amino acids long that overlap by 10 amino acids across the entirety of hAQP4. The frequency of interferon γ, interleukin (IL) 17, granulocyte-macrophage colony-stimulating factor, and IL-5-secreting CD4 + T cells was determined by the enzyme-linked immunosorbent sport assay. Quantitative immunofluorescence microscopy was performed to determine whether hAQP4 281-300 inhibits the binding of anti-hAQP4 recombinant antibody to surface full-length hAQP4. Setting: Academic neuroimmunology laboratories. Subjects: Humanized HLA-DRB1*03:01 +/+ H-2b -/- transgenic mice on a B10 background. Results: Peptide hAQP4 281-300 generated a significantly (P<.01) greater T H1 and T H17 immune response than any of the other linear peptides screened. This 20mer peptide contains 2 dominant immunogenic 15mer peptides. hAQP4 284-298 induced predominantly an IL-17 and granulocyte- macrophage colony-stimulating factor T H cell phenotype, whereas hAQP4285-299 resulted in a higher frequency of T H1 cells. hAQP4 281-300 did not interfere with recombinant AQP4 autoantibody binding. Conclusions: hAQP4 281-330 is the dominant linear immunogenic determinant of hAQP4 in the context of HLADRB1&z.ast; 03:01. Within hAQP4 281- 330 are 2 dominant immunogenic determinants that induce differential T H phenotypes. hAQP4 determinants identified in this study can serve as diagnostic biomarkers in patients with neuromyelitis optica and may facilitate the monitoring of treatment responses to pharmacotherapies.

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